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Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux

Author

Listed:
  • Lifeng Chen

    (Jinan University
    Jinan University)

  • Jingjing Zhang

    (Jinan University)

  • Weibin Xu

    (Jinan University)

  • Jiayi Chen

    (Jinan University)

  • Yujun Tang

    (Jinan University)

  • Si Xiong

    (Jinan University)

  • Yaolan Li

    (Jinan University)

  • Hong Zhang

    (Jinan University)

  • Manmei Li

    (Jinan University)

  • Zhong Liu

    (Jinan University
    Jinan University)

Abstract

Respiratory syncytial virus (RSV) hijacks cholesterol or autophagy pathways to facilitate optimal replication. However, our understanding of the associated molecular mechanisms remains limited. Here, we show that RSV infection blocks cholesterol transport from lysosomes to the endoplasmic reticulum by downregulating the activity of lysosomal acid lipase, activates the SREBP2–LDLR axis, and promotes uptake and accumulation of exogenous cholesterol in lysosomes. High cholesterol levels impair the VAP-A-binding activity of ORP1L and promote the recruitment of dynein–dynactin, PLEKHM1, or HOPS VPS39 to Rab7–RILP, thereby facilitating minus-end transport of autophagosomes and autolysosome formation. Acidification inhibition and dysfunction of cholesterol-rich lysosomes impair autophagy flux by inhibiting autolysosome degradation, which promotes the accumulation of RSV fusion protein. RSV-F storage is nearly abolished after cholesterol depletion or knockdown of LDLR. Most importantly, the knockout of LDLR effectively inhibits RSV infection in vivo. These findings elucidate the molecular mechanism of how RSV co-regulates lysosomal cholesterol reprogramming and autophagy and reveal LDLR as a novel target for anti-RSV drug development.

Suggested Citation

  • Lifeng Chen & Jingjing Zhang & Weibin Xu & Jiayi Chen & Yujun Tang & Si Xiong & Yaolan Li & Hong Zhang & Manmei Li & Zhong Liu, 2024. "Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50711-4
    DOI: 10.1038/s41467-024-50711-4
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    References listed on IDEAS

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    1. Ruud H. Wijdeven & Hans Janssen & Leila Nahidiazar & Lennert Janssen & Kees Jalink & Ilana Berlin & Jacques Neefjes, 2016. "Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
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